4-Alkyl-2-haloaniline derivative and process and process for producing the same

ABSTRACT

The present invention relates to a compound of formula (1), wherein R 1 , R 2 , R 3 , n, and X are as defined in the specification, and a process for producing the same. This compound is useful as an intermediate for the synthesis of compounds useful as pharmaceuticals or agricultural chemicals.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to 4-alkyl-2-haloaniline derivatives and aprocess for producing the same. The 4-alkyl-2-haloaniline derivativesare intermediates for the synthesis of compounds useful aspharmaceuticals or agricultural chemicals.

2. Related Art

It is known that a Friedel-Crafts alkylation reaction of an anilinederivative does not proceed without difficulty. The reason for thisdifficulty is as follows. In general, in the Friedel-Crafts alkylationreaction of an aniline derivative, a protonic acid or a Lewis acid isused as a catalyst. This catalyst, together with an amino group in theaniline derivative, forms a salt or coordinate bond to lower electrondensity on the aromatic ring, resulting in lowered reaction rate. Inparticular, it is known that, in the alkylation of a 2-haloanilinederivative, an electron withdrawing substituent effect of a halogen atomin an ortho position on the aromatic ring relative to the amino groupmakes it very difficult for the alkylation reaction to proceed.

In order to solve the above problem, two methods have been proposed.

In one of the two methods, the amino group in the 2-haloanilinederivative is first protected with a protective group, such as acetyl,to lower the capability of the amino group that the amino group combineswith the protonic acid or the Lewis acid to form a salt or complex bond.Thereafter, the Friedel-Crafts alkylation of the protected 2-haloanilinederivative is carried out. So far as the present inventors know,however, there is no report about successful preparation of a product inwhich the regioselectivity has been significantly enhanced by thismethod.

The other method is disclosed in Japanese Patent Laid-Open PublicationNo. 944/1983. In this method, a 2-haloaniline derivative is alkylated ina closed vessel at a high temperature of 175 to 250° C. under a pressureof 5 to 50 atm to selectively prepare a derivative in which an alkylgroup has been introduced into the para or ortho position of the2-haloaniline derivative.

In this method, however, the alkylation should be carried out underacidic conditions and, at the same time, under high temperature and highpressure conditions. For this reason, in carrying out the reaction, apressure-resistant and acid-resistant closed vessel should be used. Thisis disadvantageous from the viewpoint of handleability on a commercialscale. Due to the above reaction conditions, substrates usable in thisreaction are disadvantageously limited to highly thermally stablecompounds. Further, in aromatic ring coupling reactions such as Stillcoupling and Suzuki coupling, which have recently drawn attractiveattention, aromatic iodine compounds having low thermal stability aregenerally used. Therefore, the method described in Japanese PatentLaid-Open Publication No. 944/1983, which requires high temperatureconditions, cannot be applied to such iodine compounds withoutdifficulties.

Accordingly, a method for synthesizing an alkylation product under mildreaction conditions without the necessity of adopting severe reactionconditions has been desired.

On the other hand, for example, WO 01/92231 discloses6-t-butyl-8-fluoroquinoline derivatives as a group of compounds havingexcellent control activity against rice blast. Thus,4-alkyl-2-haloaniline derivatives can be used as intermediates for thesynthesis of pharmaceuticals or agricultural chemicals. When a4-alkyl-2-haloaniline derivative is synthesized for use in the aboveapplications, the 4-alkyl-2-haloaniline derivative is preferablyprepared by an alkylation reaction with high regioselectivity from theviewpoints of the quality and productivity of the final product.

SUMMARY OF THE INVENTION

The present inventors have now found that a 2-haloaniline derivative canbe alkylated under milder reaction conditions than the prior art methodby previously protecting an amino group, directly attached to thearomatic ring of a 2-haloaniline derivative, with a carbamate-typeprotective group, such as an alkyloxycarbonyl group, and then carryingout a Friedel-Crafts alkylation reaction. The present inventors havefurther found that, in this case, the alkylation reaction can be allowedto proceed with high regioselectivity, that is, the 4-position of thearomatic ring in the 2-haloaniline derivative can be alkylated with highselectivity. Further, when this reaction is utilized, a6-t-butyl-8-fluoroquinoline derivative useful for control of rice blastcan be prepared by a synthesis process using the 4-alkyl-2-haloanilinederivative as an intermediate for the synthesis of the6-t-butyl-8-fluoroquinoline derivative. The present invention has beenmade based on such finding.

Accordingly, an object of the present invention is to provide aproduction process of a 4-alkyl-2-haloaniline derivative through thealkylation of a 2-haloaniline derivative, which, as compared with theprior art method, can be carried out under milder reaction conditionsand, at the same time, can realize higher regioselectivity with respectto the alkylation of the para position relative to amino in the2-haloaniline derivative.

Another object of the present invention is to provide a4-alkyl-2-haloaniline derivative which is useful as an intermediate forthe synthesis of compounds useful as pharmaceuticals or agriculturalchemicals.

According to one aspect of the present invention, there is provided acompound of formula (1):

wherein

-   -   R¹ represents branched chain C3-C10 alkyl or optionally        substituted C3-C10 cycloalkyl;    -   R² represents a halogen atom, optionally substituted straight        chain or branched chain C1-C8 alkyl, or optionally substituted        C3-C8 cycloalkyl;

R³ represents optionally substituted straight chain or branched chainC1-C8 alkyl, optionally substituted straight chain or branched chainC2-C6 alkenyl, or optionally substituted C3-C8 cycloalkyl;

-   -   n is an integer of 0 (zero) to 3; and    -   X represents a halogen atom.

According to another aspect of the present invention, there is provideda process for producing the compound of formula (1), comprising thesteps of:

-   -   providing a 2-haloaniline derivative of formula (2); and    -   reacting the 2-haloaniline derivative with an alkylating agent        in the presence of an acid catalyst in an organic solvent or        sulfuric acid to introduce group R¹, which is as defined in        formula (1), into the 4-position of the derivative, thereby        preparing the compound of formula (1):        wherein    -   R², R³, n, and X are as defined in formula (1), provided that R²        is not in the 4-position on the aromatic ring.

The use of the compound according to the present invention as anintermediate can realize with high efficiency the synthesis of6-t-butyl-8-fluoroquinoline derivatives, which are useful aspharmaceuticals or such agricultural chemicals as rice blast controlagents. Further, according to the production process of the presentinvention, the para (4) position relative to amino on the aromatic ringof the 2-haloaniline derivative can be alkylated with highregioselectivity. As a result, a 4-alkyl-2-haloalkyloxycarbonylanilinederivative is obtained, and a 4-alkyl-2-haloaniline derivative, which isgenerally difficult to produce, can be relatively easily produced withhigh efficiency by deprotecting the4-alkyl-2-haloalkyloxycarbonylaniline derivative. By virtue of this highregioselectivity, the production of undesired by-products can bereduced, and the operation efficiency of the whole process can beimproved. Further, the process of the present invention can be carriedout on a commercial scale thereby. Therefore, the alkylation of the2-haloaniline derivative can be carried out on a commercial scale.Furthermore, the production process of the present invention can becarried out under mild reaction conditions and thus can also be appliedto the alkylation of compounds having low thermal stability such as2-iodoaniline derivatives.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of Formula (1)

The term “alkyl” as used herein as a group or a part of a group meansstraight chain, branched chain, or cyclic alkyl unless otherwisespecified. Further, for example, “C1-C8” in “C1-C8 alkyl” means that thealkyl group has 1 to 8 carbon atoms.

“Branched chain C3-C8 alkyl” is preferably branched chain C3-C5 alkyl.

Examples of “branched chain C3-C8 alkyl” include isopropyl, i-butyl,t-butyl, t-amyl, and i-hexyl.

“C1-C8 alkyl” is preferably C1-C4 alkyl, more preferably C1-C3 alkyl,still more preferably C1-C2 alkyl.

Examples of “straight chain or branched chain C1-C8 alkyl” includemethyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, t-butyl, t-amyl,n-pentyl, n-hexyl, n-heptyl, and n-octyl.

“C3-C10 cycloalkyl” is preferably C4-C6 cycloalkyl, more preferablyC5-C6 cycloalkyl.

Examples of “C3-C10 cycloalkyl” include cyclopropyl, cyclopropylmethyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“C3-C8 cycloalkyl” is preferably C4-C6 cycloalkyl, more preferably C5-C6cycloalkyl.

Examples of “C3-C8 cycloalkyl” include cyclopropyl, cyclopropylmethyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“C2-C6 alkenyl” is preferably C2-C4 alkenyl, more preferably C2-C3alkenyl.

Examples of “straight chain or branched chain C2-C6 alkenyl” includevinyl, isopropenyl, and i-butenyl.

The term “halogen atom” (halide) as used herein means a fluorine,chlorine, bromine, or iodine atom.

The expression “optionally substituted” alkyl as used herein means thatone or more hydrogen atoms on alkyl may be substituted by one or moresubstituents which may be the same or different. It will be apparent toa person skilled in the art that the maximum number of substituents maybe determined depending upon the number of substitutable hydrogen atomson alkyl. This is true of alkenyl and cycloalkyl.

The substituent can be selected from the group consisting of a halogenatom, nitro, ester, straight chain or branched chain C1-C4 alkyl,straight chain or branched chain C1-C4 alkoxy, allyl, nitrophenyl, andC1-C4 alkylsulfonyl.

The term “ester” means ester having 1 to 4 carbon atoms, and examples ofthe ester include acetic esters, propionic esters, butanoic esters,isobutanoic esters, and cyclopropylcarboxylic esters.

“C1-C4 alkoxy” is preferably C1-C3 alkoxy, more preferably C1-C2 alkoxy.Examples of “C1-C4 alkoxy” include methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, i-butoxy, s-butoxy, and t-butoxy.

“C1-C4 alkylsulfonyl” is preferably C1-C3 alkylsulfonyl, more preferablyC1-C2 alkylsulfonyl. Examples of “C1-C4 alkylsulfonyl” includemethylsulfonyl, ethylsulfonyl, n-propylsulfonyl, n-butylsulfonyl,i-butylsulfonyl, and t-butylsulfonyl.

R¹ preferably represents branched chain C3-C5 alkyl or optionallysubstituted C3-C6 cycloalkyl, more preferably isopropyl, t-butyl,t-amyl, or 1-methylcyclohexyl, still more preferably isopropyl, t-butyl,or 1-methylcyclohexyl, most preferably isopropyl or t-butyl.

R²preferably represents a halogen atom or straight chain or branchedchain Cl -C4 alkyl, more preferably a halogen atom or methyl, still morepreferably a fluorine atom or methyl.

n is preferably an integer of 0 (zero) to 2, more preferably 0 (zero) or1, still more preferably 0 (zero).

In another preferred embodiment of the present invention, in formula(1), when n is 1, R² represents a fluorine atom or methyl.

When n is 1, preferably, R²is in a 3-, 5-, or 6-position relative toamino on the aromatic ring. More preferably, when n is 1 and R²represents a fluorine atom, R² is in a 3- or 6-position relative toamino on the aromatic ring. Alternatively, more preferably, when n is 1and R² represents alkyl, R² is in a 3- or 5-position relative to aminoon the aromatic ring.

R³ preferably represents optionally substituted straight chain orbranched chain C1-C4 alkyl, vinyl, isopropenyl, or optionallysubstituted C5-C6 cycloalkyl, more preferably methyl, ethyl, n-propyl,4-nitrobenzyl, 2-methylsulfonylethyl, vinyl, or isopropenyl, still morepreferably methyl or ethyl.

X preferably represents a fluorine, chlorine, or bromine atom, morepreferably a fluorine or chlorine atom, still more preferably a fluorineatom.

In a preferred embodiment of the present invention, in formula (1), R¹represents isopropyl, t-butyl, or 1-methylcyclohexyl; R³ representsmethyl or ethyl; and n is 0 (zero).

In a more preferred embodiment of the present invention, in formula (1),R¹ represents isopropyl or t-butyl; R³ represents methyl or ethyl;

-   -   n is 0 (zero); and X represents a fluorine atom.

In a still more preferred embodiment of the present invention, informula (1), R¹ represents t-butyl; R³ represents methyl or ethyl; n is0 (zero); and X represents a fluorine atom.

Specific examples of compounds of formula (1) include2-chloro-4-isopropyl-N-methoxycarbonylaniline,2-fluoro-4-isopropyl-N-methoxycarbonylaniline,2-bromo-4-isopropyl-N-methoxycarbonylaniline,2-iodo-4-isopropyl-N-methoxycarbonylaniline,2-chloro-4-isopropyl-N-ethoxycarbonylaniline,2-fluoro-4-isopropyl-N-ethoxycarbonylaniline,2-bromo-4-isopropyl-N-ethoxycarbonylaniline,2-iodo-4-isopropyl-N-ethoxycarbonylaniline,4-t-butyl-2-chloro-N-methoxycarbonylaniline,4-t-butyl-2-fluoro-N-methoxycarbonylaniline,2-bromo-4-t-butyl-N-methoxycarbonylaniline,4-t-butyl-2-iodo-N-methoxycarbonylaniline,4-t-butyl-2-chloro-N-ethoxycarbonylaniline,4-t-butyl-2-fluoro-N-ethoxycarbonylaniline,2-bromo-4-t-butyl-N-ethoxycarbonylaniline,4-t-butyl-2-iodo-N-ethoxycarbonylaniline,4-t-amyl-2-chloro-N-methoxycarbonylaniline,4-t-amyl-2-fluoro-N-methoxycarbonylaniline,4-t-amyl-2-bromo-N-methoxycarbonylaniline,4-t-amyl-2-iodo-N-methoxycarbonylaniline,4-t-amyl-2-chloro-N-ethoxycarbonylaniline,4-t-amyl-2-fluoro-N-ethoxycarbonylaniline,4-t-amyl-2-bromo-N-ethoxycarbonylaniline,4-t-amyl-2-iodo-N-ethoxycarbonylaniline,4-t-butyl-2,6-difluoro-N-methoxycarbonylaniline,4-t-butyl-2,3-difluoro-N-methoxycarbonylaniline,4-t-butyl-2,6-difluoro-N-ethoxycarbonylaniline,4-t-butyl-2,3-difluoro-N-ethoxycarbonylaniline,4-t-butyl-2-fluoro-3-methyl-N-methoxycarbonylaniline,4-t-butyl-2-fluoro-5-methyl-N-methoxycarbonylaniline,4-t-butyl-2-fluoro-3-methyl-N-ethoxycarbonylaniline,4-t-butyl-2-fluoro-5-methyl-N-ethoxycarbonylaniline,2-fluoro-4-(1-methylcyclohexyl)-N-methoxycarbonylaniline,2-fluoro-4-(1-methylcyclohexyl)-N-ethoxycarbonylaniline,2-chloro-4-(1-methylcyclohexyl)-N-methoxycarbonylaniline,2-chloro-4-(1-methylcyclohexyl)-N-ethoxycarbonylaniline,2-bromo-4-(1-methylcyclohexyl)-N-methoxycarbonylaniline, and2-bromo-4-(1-methylcyclohexyl)-N-ethoxycarbonylaniline.

Examples of preferred compounds of formula (1) include2-fluoro-4-(1-methylcyclohexyl)-N-methoxycarbonylaniline,2-fluoro-4-(1-methylcyclohexyl)-N-ethoxycarbonylaniline,4-t-butyl-2-fluoro-N-methoxycarbonylaniline, and4-t-butyl-2-fluoro-N-ethoxycarbonylaniline.

Production of Compounds of Formula (1)

Compounds of formula (1) according to the present invention may beproduced, for example, according to scheme 1. Starting compounds ormaterials necessary for the synthesis of the compounds according to thepresent invention are commercially available or can be easily producedby a conventional method.

wherein

-   -   R¹, R², R³, n, and X are as defined in formula (1)    -   provided that R² is not in the 4-position on the aromatic ring        in formulae (2) and (4).

Steps in scheme 1 will be described in detail in order.

Step (a):

A 2-haloaniline derivative of formula (2) can be prepared by reacting acompound of formula (4) or its salt with a chloroformic ester ClCOOR³,wherein R³ is as defined in formula (1), under basic conditions toprotect amino in the compound of formula (4) or its salt.

Bases usable for providing basic conditions include, for example,pyridine, triethylamine, trimethylamine, morpholine, potassiumcarbonate, and sodium carbonate.

Specific examples of compounds of formula (4) as the starting compoundinclude: 2-fluoroaniline, 2-chloroaniline, 2-bromoaniline,2-iodoaniline, 2,6-difluoroaniline, and 2,3-difluoroaniline and saltsthereof; 2-fluoro-3-methylaniline; and 2-fluoro-5-methylaniline.

Chloroformic esters usable herein include, for example, alkylchloroformates, for example, methyl chloroformate, ethyl chloroformate,and alkenyl chloroformates, for example, allyl chloroformate.

The protection reaction of the compound of formula (4) or its salt withthe chloroformic ester can be allowed to proceed by causing asubstitution reaction in a solvent, such as ethyl acetate, toluene, ortetrahydrofuran, for example, at a temperature of −20° C. to the boilingtemperature of the solvent, preferably 0 (zero) to 50° C.

In this reaction, the amino group in the compound of formula (4) isprotected with a protective group, for example, alkyloxycarbonyl,alkenyloxycarbonyl, 4-nitrobenzyloxycarbonyl, or2-methylsulfonylethyloxycarbonyl, to give the 2-haloaniline derivativeof formula (2).

Thus, when a carbamate-type protective group such as alkyloxycarbonyl isused, only the para position (4-position) relative to amino attached tothe aromatic ring can be selectively alkylated. When other protectivegroups, for example, amide-type protective groups such as formyl,acetyl, and pivaloyl, are used, in general, disadvantageously, 5-alkylcompounds, which are compounds substituted at the meta position relativeto amino attached to the aromatic ring, are mainly produced due to paraorientation domination of 2-substituted halogen.

Specific examples of 2-haloaniline derivatives of formula (2) include2-fluoro-N-methoxycarbonylaniline, 2-chloro-N-methoxycarbonylaniline,2-bromo-N-methoxycarbonylaniline, 2-iodo-N-methoxycarbonylaniline,2-fluoro-N-ethoxycarbonylaniline, 2-chloro-N-ethoxycarbonylaniline,2-bromo-N-ethoxycarbonylaniline, 2-iodo-N-ethoxycarbonylaniline,2,6-difluoro-N-methoxycarbonylaniline,2,3-difluoro-N-methoxycarbonylaniline,2,6-difluoro-N-ethoxycarbonylaniline,2,3-difluoro-N-ethoxycarbonylaniline,2-fluoro-3-methyl-N-methoxycarbonylaniline, and2-fluoro-5-methyl-N-methoxycarbonylaniline.

Step (b):

Compounds of formula (1) can be produced by introducing various alkylgroups into a 2-haloaniline derivative of formula (2) under conventionalFriedel-Crafts alkylation conditions. More specifically, a compound offormula (1) can be produced by reacting a 2-haloaniline derivative offormula (2) with an alkylating agent in the presence of an acid catalystin an organic solvent or sulfuric acid to introduce group R¹, wherein R¹is as defined in formula (1), into the 4-position of the derivative.

The 2-haloaniline derivative of formula (2) may be one produced in step(a), or alternatively may be a commercially available one.

Alkylating agents usable herein include, for example, n-propyl chloride,n-propyl alcohol, isopropyl chloride, isopropyl bromide, isopropylalcohol, 1-propene, isobutyl chloride, isobutyl bromide, t-butylalcohol, isobutene, t-butyl chloride, t-butyl bromide,2-methyl-l-butene, 2-methyl-2-butene, t-amyl alcohol, t-amyl chloride,t-amyl bromide, 1-chloro-2-methylbutane, 1-bromo-2-methylbutane, and4-propyl-4-heptanol.

In a preferred embodiment of the present invention, the alkylating agentis selected from the group consisting of t-butyl alcohol, isobutene,t-butyl chloride, t-butyl bromide, isobutyl bromide, and isobutylchloride. More preferably, the alkylating agent is selected from t-butylalcohol or isobutyl bromide.

For example, when t-butyl is introduced into the derivative of formula(2), the alkylating agent is preferably t-butyl alcohol or isobutylbromide.

The amount of the alkylating agent used may be properly varied, forexample, depending upon the structure and amount of the derivative offormula (2) and the structure of the alkylating agent used. For example,when t-butyl alcohol is used as the alkylating agent, the amount oft-butyl alcohol used is preferably 1.0 to 5.0 moles, more preferably 1.0to 4.0 moles, based on one mole of the derivative of formula (2).

Preferred acid catalysts include protonic acids and Lewis acids.

A typical example of the protonic acid catalyst is concentrated sulfuricacid. A typical example of the Lewis acid catalyst is anhydrous aluminumchloride. Sulfuric acid which has been diluted with water to a suitableconcentration, for example, 50 to 90% sulfuric acid, may also be used asthe protonic acid catalyst. Other acid catalysts usable herein include,for example, protonic acids, Lewis acids, or resin catalysts commonlyused in conventional Friedel-Crafts reactions, for example, concentratedhydrochloric acid, concentrated nitric acid, stannic chloride, zincchloride, ferric chloride, and strongly acidic ion exchange resin,Nafion-H resin or other resins.

For example, when t-butyl is introduced into the derivative of formula(2), the use of either a combination of anhydrous aluminum chloride asthe acid catalyst with isobutyl bromide as the alkylating agent or acombination of 50 to 90% sulfuric acid as the acid catalyst with t-butylalcohol as the alkylating agent is preferred. When t-butyl is introducedinto the derivative of formula (2), more preferably, a combination of 70to 80% sulfuric acid as the acid catalyst with t-butyl alcohol as thealkylating agent is used.

Step (b) may be carried out in the absence of a solvent. Preferably,however, step (b) is carried out in a suitable solvent.

When anhydrous aluminum chloride, which is a Lewis acid, is used as theacid catalyst, the solvent is preferably a chlorine-containing solventsuch as methylene chloride, chloroform, or tetrachloroethane. In somecases, carbon disulfide or nitrobenzene commonly used in conventionalFriedel-Crafts reactions may not be suitable as the solvent.

When concentrated sulfuric acid, which is a protonic acid, is used asthe acid catalyst, the concentrated sulfuric acid may also be used asthe solvent. In this case, the concentration of the concentratedsulfuric acid is preferably 50 to 90% (w/w), more preferably 70 to 90%(w/w). When concentrated sulfuric acid as such is used, in some cases,large amounts of by-products may be produced, resulting in lowered yieldof the target compound.

The amount of the acid catalyst used is preferably 1.5 to 4.0 moles,more preferably 2.0 to 3.0 moles, based on one mole of the derivative offormula (2). This, however, does not apply to the case where a protonicacid such as concentrated sulfuric acid or concentrated hydrochloricacid is used both as the acid catalyst and the solvent.

Step (b) will be described in more details for each acid catalyst type.

When aluminum chloride, which is a Lewis acid, is used as the acidcatalyst, step (b) is desirably carried out by providing a mixedsolution composed of the derivative of formula (2) dissolved in asolvent, adding aluminum chloride to the mixed solution, heating themixture at 40 to 60° C. for 30 min to dissolve aluminum chloride in themixed solution, then cooling the mixed solution to room temperature,adding an alkylating agent thereto, and allowing a reaction to proceed.

In this case, the amount of the alkylating agent used is preferably 1.0to 6.0 moles, more preferably 4.5 to 5.5 moles, based on one mole of thederivative of formula (2). In the reaction, the alkylating agent may beadded to the mixed solution at a time, or alternatively may beintroduced in two or more divided portions into the reaction system.Preferably, in the reaction, the alkylating agent is added dropwise tothe reaction system over a period of 15 to 30 min.

The optimal reaction temperature varies in the range of a temperatureprovided under ice cooling to 40° C. depending upon the type of solvent.Therefore, the reaction temperature may be properly varied dependingupon the solvent. In general, however, the reaction is preferablycarried out at room temperature (for example 20 to 30° C.) from theviewpoint of yield. The reaction time is generally 1 to 4 hr. Thedisappearance of the evolution of resulting hydrochloric acid gas may beindicative of the completion of the reaction. The resulting hydrochloricacid gas can be efficiently removed from the reaction system by bubblinginert gas, such as nitrogen gas or argon gas, into the reaction system.The bubbling generally can have good effect on yield.

After the completion of the reaction, water or a hydrochloric acidsolution is added to the reaction solution to decompose the Lewis acidused as the catalyst, such as aluminum chloride, zinc chloride, orstannic chloride. Subsequently, the reaction solution is extracted witha solvent, which is the same as the reaction solvent, or a nonpolarsolvent, such as n-hexane, n-pentane, or ethyl acetate, to give thecompound of formula (1) as the target compound. After the removal of thesolvent from the extract by distillation, the compound thus obtained assuch may be used in the next reaction. Alternatively, the compound maybe purified, for example, by distillation or column chromatography onsilica gel.

When concentrated sulfuric acid, which is a protonic acid, is used bothas the acid catalyst and the solvent, a method is preferably adoptedwherein an alkylating agent is added to a mixed solution composed of thederivative of formula (2) dissolved in concentrated sulfuric acid and areaction is allowed to proceed.

Preferred alkylating agents include, for example, isopropyl bromide andt-butyl bromide and, further, alcohols such as isopropyl alcohol andt-butyl alcohol. In this case, preferably, the alkylating agent is usedin an amount of 1.0 to 5.0 moles, more preferably 2.5 to 4.0 moles,based on one mole of the derivative of formula (2). In the reaction, thealkylating agent may be added to the mixed solution either at a time, oralternatively may be introduced in two or more divided portions into thereaction system. Preferably, in the reaction, the alkylating agent isadded in three or more divided portions.

The reaction temperature is generally in the range of 50 to 80° C.,preferably in the range of 60 to 80° C. The reaction time is generally 3to 6 hr, preferably 4 to 5 hr.

After the completion of the reaction, the reaction solution is extractedwith a solvent such as n-hexane, n-pentane, or a ethyl acetate-n-hexanemixed solution to give the compound of formula (1) as the targetcompound. After the removal of the solvent from the extract bydistillation, the compound thus obtained as such may be used in the nextreaction. Alternatively, the compound may be purified, for example, bydistillation or column chromatography on silica gel.

Step (c):

The protected amino in the compound of formula (1) is deprotected underacidic or basic conditions to give an aniline derivative of formula (3)or a pharmaceutically acceptable salt or solvate thereof. Thedeprotection reaction can be carried out by a person having ordinaryskill in the art by a conventional method properly selected dependingupon the type of the protective group.

For example, when the protective group is alkyloxycarbonyl,substantially quantitative deprotection can be achieved by dissolvingthe compound of formula (1) in a water-soluble polar solvent, such asmethanol or ethanol, adding a 5 to 53% aqueous sodium hydroxide solutionor a 5 to 47% aqueous potassium hydroxide solution, and heating themixture with stirring. The concentration of the aqueous potassiumhydroxide solution or the aqueous sodium hydroxide solution ispreferably about 30% from the view point of stirring operation. Thisreaction may also be carried out in the absence of the above solvent. Inthis case, a 5 to 53%, preferably 20 to 53%, particularly preferablyabout 30%, aqueous sodium hydroxide solution, or a 5 to 47%, preferably20 to 47%, particularly preferably about 30%, aqueous potassiumhydroxide solution may be used. As described above, for both the aqueoussodium hydroxide solution and the aqueous potassium hydroxide solution,the concentration is preferably about 30% from the viewpoint of stirringoperation. Further, in this case, even under conditions other than theabove basic conditions, for example, catalytic hydrogenation conditionsusing palladium or platinum oxide, the compound of formula (1) can bequantitatively deprotected.

Accordingly, in a preferred embodiment of the present invention, thereis provided a process for producing an aniline derivative of formula (3)or a pharmaceutically acceptable salt or solvate thereof, said processcomprising the steps of: adding, for example, a 20 to 53% aqueous sodiumhydroxide solution or a 20 to 47% aqueous potassium hydroxide solutionto the compound of formula (1) in the presence of an organic solvent,such as methanol or ethanol, or in the absence of any solvent; and heattreating the mixture optionally under suitable deprotection conditions.

When the protective group is alkenyloxycarbonyl, the compound of formula(1) can be substantially quantitatively deprotected by carrying out theheat treatment in a 47% hydrobromic acid-acetic acid solution.

Specific examples of aniline derivatives of formula (3) produced in step(c) include: 2-fluoro-4-isopropylaniline, 2-chloro-4-isopropylaniline,2-bromo-4-isopropylaniline, 2-iodo-4-isopropylaniline,4-t-butyl-2-fluoroaniline, 4-t-butyl-2-chloroaniline,2-bromo-4-t-butylaniline, 4-t-butyl-2-iodoaniline,4-t-amyl-2-fluoroaniline, 4-t-amyl-2-chloroaniline,4-t-amyl-2-bromoaniline, 4-t-amyl-2-iodoaniline,4-t-butyl-2,6-difluoroaniline, 4-t-butyl-2,3-difluoroaniline,4-t-butyl-2-fluoro-3-methylaniline, and4-t-butyl-2-fluoro-5-methylaniline.

The compounds according to the present invention may formpharmaceutically acceptable salts thereof. Preferred examples of suchsalts include: hydrohalogenide salts such as hydrochloride salts,hydrobromide salts, or hydroiodide salts; inorganic acid salts such asnitric acid salts, perchloric acid salts, sulfuric acid salts, orphosphoric acid salts; lower alkylsulfonic acid salts such asmethanesulfonic acid salts, trifluoromethanesulfonic acid salts, orethanesulfonic acid salts; arylsulfonic acid salts such asbenzenesulfonic acid salts or p-toluenesulfonic acid salts; organic acidsalts such as fumaric acid salts, succinic acid salts, citric acidsalts, tartaric acid salts, oxalic acid salts, or maleic acid salts; andamino acid salts such as glutamic acid salts or aspartic acid salts.

Further, in the present invention, the compounds may form solvates, andexamples thereof include hydrates, alcoholates, for example,methanolates or ethanolates, and etherates, for example, diethyletherates.

Applications of Compounds of Formula (1)

The compounds of formula (1) according to the present invention areintermediates for the synthesis of compounds useful as pharmaceuticalsor agricultural chemicals.

6-t-Butyl-8-fluoroquinoline derivatives having excellent controlactivity against rice blast can be easily produced from the compound offormula (1) according to the present invention or the derivative offormula (3) produced from the compound of formula (1) by the synthesismethod described in WO 01/92231 or the method described in J. Chem.Soc., (C). 2426 (1970) or Tetrahedron Lett., 4945 (1968). That the6-t-butyl-8-fluoroquinoline derivatives thus obtained are a group ofcompounds having excellent control activity against rice blast is asdisclosed in WO 01/92231.

For example, 6-t-butyl-2,3-dimethyl-8-fluoroquinolone can be produced bydehydrocondensing 4-t-butyl-2-fluoroaniline produced by the presentinvention or its salt with ethyl 2-methylacetoacetate by the synthesismethod described in WO 01/92231 or the method described in J. Chem.Soc., (C). 2426 (1970) or Tetrahedron Lett., 4945 (1968) to give aSchiff base compound and heating the Schiff base compound in phenylether at 250° C. to cyclize the compound into a quinolone ring.4-Acetoxy-6-t-butyl-2,3-dimethyl-8-fluoroquinoline can be produced byconverting this quinolone compound under acetic anhydride-baseconditions to 4-o-acetylquinoline. As described in WO 01/92231, thiscompound has excellent control activity against rice blast.

A synthesis process of 6-t-butyl-8-fluoroquinoline derivative(hereinafter often referred to as “compound of formula (i)”) describedin WO 01/92231, wherein the derivative of formula (3) produced accordingto the present invention (particularly 4-t-butyl-2-fluoroaniline) isused as the starting compound, will be specifically described.

The compound of formula (i) can be produced, for example, according toscheme 2 from 4-t-butyl-2-fluoroaniline synthesizable by a known method.

wherein

-   -   R^(a) represents a hydrogen atom, —COR¹¹, —COOR¹¹, —COCH₂OCH₃,        or —COCH₂OCOCH₃;    -   R¹¹ represents alkyl having 1 to 4 carbon atoms; and    -   R¹² represents —R¹¹, —OR¹¹, —CH₂OCH₃, or —CH₂OCOCH₃.

In this scheme 2, a compound of formula (ii) is first provided (step(d)). Next, if necessary, the compound of formula (ii) is reacted withthe compound of formula (iii) or (iv) in the presence or absence of abase (step (e)) to give the compound of formula (i).

Scheme 2 will be described in more detail.

Step (d):

A compound of formula (ii) is first produced from4-t-butyl-2-fluoroaniline and ethyl 2-methylacetoacetate, for example,according to the method described in J. Am. Chem. Soc. 70, 2402 (1948)or Tetrahedron Lett. 27, 5323 (1986). The compound of formula (ii)corresponds to the compound of formula (i) wherein R^(a) represents ahydrogen atom. 4-t-Butyl-2-fluoroaniline used can be produced by aconventional method described, for example, in Chem. Abs. 42, 2239 or J.Chem. Soc., Chem. Commun., 1992, 595.

Step (e):

Next, when a compound of formula (i), wherein R^(a) represents a groupother than a hydrogen atom, is desired, the compound of formula (i) canbe produced by reacting the compound of formula (ii) with a compound offormula (iii) or (iv) in the presence or absence of a base.

Bases usable herein include, for example, organic amines, such astriethylamine and pyridine, and inorganic bases such as sodiumcarbonate, potassium carbonate, and sodium hydride. The compound offormula (iii) or (iv) is preferably used in an amount of 1 to 50equivalents, more preferably 1 to 10 equivalents, based on the compoundof formula (ii). The reaction in step (e) can be carried out in anorganic solvent in the absence of a solvent or in an organic solventinert to the reaction, for example, dimethylformamide ortetrahydrofuran, for example, at a temperature in the range of 0 (zero)to 140° C.

EXAMPLES

The following examples further illustrate the present invention, but arenot intended to limit it.

Example 1 1-a) Synthesis of 2-fluoro-N-methoxycarbonylaniline

2-Fluoroaniline (10.0 mL, 0.104 mol) was dissolved in ethyl acetate (40mL) to prepare a solution. Pyridine (10.0 mL, 0.124 mol) was added tothe solution, and the mixture was cooled under ice cooling. A solutionof methyl chloroformate (8.80 mL, 0.114 mol) in 10 mL of ethyl acetatewas added dropwise to the cooled mixture over a period of 30 min. Thereaction solution was warmed to room temperature followed by stirringfor 3 hr. The disappearance of 2-fluoroaniline from the reactionsolution was confirmed by high performance liquid chromatography.Thereafter, 20 mL of water was added thereto under ice cooling to stopthe reaction. Next, 50 mL of ethyl acetate and 50 mL of water were addedto the reaction mixture to carry out extraction. The organic layer waswashed with 40 mL of water and 30 mL of a saturated sodiumhydrogencarbonate solution and was then dried over an hydrous magnesiumsulfate. The solvent was then removed from the organic layer bydistillation to give 16.5 g of 2-fluoro-N-methoxycarbonylaniline as asubstantially single product (yield 94.4%).

EI-MS: m/z 170 (M+H)⁺; ¹H NMR (CDCl₃) δ 3.80 (3H, s, CH₃), 6.86 (1H, bs,NH), 6.97-7.09 (2H, m, H₄ and H₅), 7.12 (1H, t-like, J=7.3 Hz, H₃), 8.08(1H, bs, H₆).

1-b) Synthesis of 4-t-butyl-2-fluoro-N-methoxycarbonylaniline usingisobutyl bromide

2-Fluoro-N-methoxycarbonylaniline (500 mg, 3.11 mmol) was dissolved inmethylene chloride (20 mL) to prepare a solution. Anhydrous aluminumchloride (986 mg, 7.77 mmol) was added to the solution, and the mixturewas stirred at 40° C. for 20 min. Thereafter, the reaction solution wascooled to room temperature. A solution of isobutyl bromide (1.60 mL,15.5 mmol) in a methylene chloride solution (6 mL) was added dropwise tothe cooled reaction mixture while bubbling argon gas over a period of 10min. The mixture was stirred for one hr. Water was added thereto,followed by separation of an organic layer. The organic layer was washedwith water and was dried over anhydrous magnesium sulfate. The solventwas then removed from the dried organic layer by distillation to give779 mg of 4-t-butyl-2-fluoro-N-methoxycarbonylaniline as a crudeproduct. The crude product was further subjected to separation andpurification by column chromatography on silica gel to give 433 mg of4-t-butyl-2-fluoro-N-methoxycarbonylaniline (yield 64.0%, 4-t-butylform: 5-t-butyl form=88:12).

EI-MS:m/z226(M+H)⁺; ¹H NMR (CDCl₃) δ 1.31 (9H, s, t-Bu), 3.80 (3H, s,CH₃), 6.76 (1H, bs, NH), 7.08 (1H, dd, J=13.1, 2.1 Hz, H₃), 7.13 (1H,dd, J=8.2, 1.4 Hz, H₅), 7.94 (1H, bs, H₆).

1-b′) Synthesis of 4-t-butyl-2-fluoro-N-methoxycarbonylaniline usingsulfuric acid

2-Fluoro-N-methoxycarbonylaniline (150 g, 0.859 mol) was dissolved in77.6% sulfuric acid (206 g) to prepare a solution. t-Butyl alcohol (72.9g, 1.07 mol) was added dropwise to the solution under a nitrogenatmosphere over a period of 30 min while stirring and heating thesolution at 70° C. After the completion of the dropwise addition, thereaction solution was vigorously stirred at the same temperature for onehr. t-Butyl alcohol (72.9 g, 1.07 mol) was again added dropwise theretoover a period of 30 min. After the completion of the dropwise addition,the reaction solution was vigorously stirred at the same temperature forone hr. t-Butyl alcohol (72.9 g, 1.07 mol) was again added dropwisethereto over a period of 30 min. After the completion of the dropwiseaddition, the reaction solution was vigorously stirred at the sametemperature for one hr. The reaction solution was cooled to roomtemperature. n-Hexane (530 mL) was then added to the cooled reactionsolution to carry out extraction for separation of the mixture into asulfuric acid layer and an organic layer. n-Hexane (530 mL) was againadded to the sulfuric acid layer to carry out extraction for separationof an organic layer. The organic layers thus obtained were combined, andthe combined organic layer was washed with water and saturated brine inthat order. The solvent was then removed from the organic layer bydistillation to give 307 g of4-t-butyl-2-fluoro-N-methoxycarbonylaniline as an oily crude product(yield on weight basis 159%, purity as determined by gas chromatography65.1%, 4-t-butyl form 5-t-butyl form=100:0).

FAB-MS: m/z 226 (M+H)⁺; ¹H NMR (CDCl₃) δ 3.75 (3H, s), 7.05 (3H, m),8.05 (1H, m).

1-c) Synthesis of 4-t-butyl-2-fluoroaniline

To 303 g of 4-t-butyl-2-fluoro-N-methoxycarbonylaniline as the crudeproduct was added 657 g of a 30% aqueous sodium hydroxide solution. Themixture was heated under reflux at a temperature around 90° C. for 4 hrand was allowed to cool. Water (1,000 mL) was then added thereto, andthe mixture was extracted four times with 500 mL of hexane. The organiclayers thus obtained were combined, and 2 M hydrochloric acid was addedthereto, followed by vigorous stirring to convert the amino group to ahydrochloride form. Subsequently, an aqueous layer was separated and wasadjusted to pH 9 by the addition of aqueous sodium hydroxide solution tobring the amino group to a free form. Extraction was carried out twicewith 1,000 mL of toluene. The organic layers thus obtained werecombined, and the combined organic layer was washed with saturatedbrine. The solvent was then removed from the organic layer bydistillation to give 92.9 g of 4-t-butyl-2-fluoroaniline as an oilysubstantially single product (yield 65.6% (yield in two steps oft-butylation-deprotection)).

EI-MS: m/z 170 (M+H)⁺; ¹H NMR (CDCl₃) δ 1.26 (9H, s, t-Bu), 3.56 (br,NH₂), 6.74 (1H, t-like, J=9.3 Hz, H₆), 6.95 (1H, ddd, J=7.5, 2.1, 0.7Hz, H₅), 7.94 (1H, dd, J=13.4, 1.9 Hz, H₃).

Example 2 Synthesis of 4-t-butyl-2-chloro-N-methoxycarbonylaniline

2-Chloro-N-methoxycarbonylaniline (3.00 g, 16.2 mmol) derived fromcommercially available 2-chloroaniline was dissolved in 77.6%sulfuricacid (24.0 g) to prepare a solution. t-Butyl alcohol (1.7 mL,17.8 mmol) was added dropwise to the solution under a nitrogenatmosphere over a period of 30 min while stirring and heating thesolution at 70° C. After the completion of the dropwise addition, thereaction solution was vigorously stirred at the same temperature for onehr. Thereafter, t-butyl alcohol (1.7 mL, 17.8 mmol) was again addeddropwise thereto over a period of 30 min. After the completion of thedropwise addition, the reaction solution was vigorously stirred at thesame temperature for one hr. t-Butyl alcohol (1.7 mL, 17.8 mmol) wasagain added dropwise thereto over a period of 30 min. After thecompletion of the dropwise addition, the reaction solution wasvigorously stirred at the same temperature for one hr. The reactionsolution was cooled to room temperature. n-Hexane (12 mL) was then addedthereto to carry out extraction for separation of the mixture into asulfuric acid layer and an organic layer. n-Hexane (12 mL) was againadded to the sulfuric acid layer to carry out extraction for separationof an organic layer. The organic layers thus obtained were combined, andthe combined organic layer was washed with water, a saturated aqueoussodium hydrogencarbonate solution, and water in that order. The solventwas then removed from the organic layer by distillation under thereduced pressure to give 4.00 g of a light yellow oil. The oil wasfurther subjected to separation and purification by columnchromatography on silica gel to give 2.12 g of4-t-butyl-2-chloro-N-methoxycarbonylaniline as a target compound (yield49.5%, 4-t-butyl form: 5-t-butyl form=91:9).

EI-MS: m/z 241 (M)⁺; ¹H NMR (CDCl₃) δ 1.29 (9H, s, t-Bu), 3.80 (3H, s,CH₃), 7.05 (1H, bs, NH), 7.28 (1H, dd, J=8.5, 2.1 Hz, H₅), 7.34 (1H, d,J=2.2 Hz, H₃), 8.03 (1H, bd, J=8.3 Hz, H₆).

Example 3 Synthesis of 2-bromo-4-t-butyl-N-methoxycarbonylaniline

2-Bromo-N-methoxycarbonylaniline (3.00 g, 13.0 mmol) derived fromcommercially available 2-bromoaniline was dissolved in 77.6% sulfuricacid (19.0 g) to prepare a solution. t-Butyl alcohol (1.40 mL, 14.3mmol) was added dropwise to the solution under a nitrogen atmosphereover a period of 30 min while stirring and heating the solution at 70°C. After the completion of the dropwise addition, the reaction solutionwas vigorously stirred at the same temperature for one hr. Thereafter,t-butyl alcohol (1.40 mL, 14.3 mmol) was again added dropwise theretoover a period of 30 min. After the completion of the dropwise addition,the reaction solution was vigorously stirred at the same temperature forone hr. t-Butyl alcohol (1.40 mL, 14.3 mmol) was again added dropwisethereto over a period of 30 min. After the completion of the dropwiseaddition, the reaction solution was vigorously stirred at the sametemperature for one hr. The reaction solution was cooled to roomtemperature. n-Hexane (10 mL) was then added to the cooled reactionsolution to carry out extraction for separation of the mixture into asulfuric acid layer and an organic layer. n-Hexane (10 mL) was againadded to the sulfuric acid layer to carry out extraction for separationof an organic layer. The organic layers thus obtained were combined, andthe combined organic layer was washed with water, a saturated aqueoussodium hydrogencarbonate solution, and water in that order. The solventwas then removed from the organic layer by distillation under thereduced pressure to give 4.20 g of light yellow oil. The oil was furthersubjected to separation and purification by column chromatography onsilica gel to give 2.08 g of 2-bromo-4-t-butyl-N-methoxycarbonylanilineas a target compound (yield 55.8%, 4-t-butyl form: 5-t-butyl form=92:8).

EI-MS: m/z 285 (M)⁺; ¹H NMR (CDCl₃) δ 1.29 (9H, s, t-Bu) 3.80 (3H, s,CH₃), 7.04 (1H, bs, NH), 7.33 (1H, dd, J=8.7, 2.2 Hz, H₅), 7.50 (1H, d,J=2.2 Hz, H₃), 8.01 (1H, bd, J=8.0 Hz, H₆).

Example 4 Synthesis of 4-t-butyl-2-iodo-N-methoxycarbonylaniline

2-Iodo-N-methoxycarbonylaniline (2.00 g, 7.22 mmol) derived fromcommercially available 2-iodoaniline was dissolved in 77.6% sulfuricacid (11.0 g) to prepare a solution. t-Butyl alcohol (2.10 mL, 21.7mmol) was added dropwise to the solution under a nitrogen atmosphereover a period of 10 min while stirring and heating the solution at 60°C. After the completion of the dropwise addition, the reaction solutionwas vigorously stirred at the same temperature for 30 min. The reactionsolution was cooled to room temperature. n-Hexane (20 mL) was then addedto the cooled reaction solution to carry out extraction for separationof the mixture into a sulfuric acid layer and an organic layer. n-Hexane(20 mL) was again added to the sulfuric acid layer to carry outextraction for separation of an organic layer. The organic layers thusobtained were combined, and the combined organic layer was washed withwater, a saturated aqueous sodium hydrogencarbonate solution, and waterin that order. The solvent was then removed from the organic layer bydistillation under the reduced pressure to give 1.36 g of a light brownoil. The oil was further subjected to separation and purification bycolumn chromatography on silica gel to give 0.790 g of4-t-butyl-2-iodo-N-methoxycarbonylaniline as a target compound (yield32.8%, 4-t-butyl form: 5-t-butyl form=94:6).

EI-MS: m/z 333 (M)⁺; ¹H NMR (CDCl₃) δ 1.29 (9H, s, t-Bu), 3.80 (3H, s,CH₃), 6.87 (1H, bs, NH), 7.36 (1H, dd, J=8.2, 2.2 Hz, H₅), 7.73 (1H, d,J=2.2 Hz, H₃), 7.90 (1H, bd, J=8.8 Hz, H₆).

Example 5 Synthesis of 2-fluoro-4-isopropyl-N-methoxycarbonylaniline

2-Fluoro-N-methoxycarbonylaniline (1.00 g, 5.92 mmol) prepared asdescribed in Example 1 was dissolved in 77.6% sulfuric acid (5.00 g) toprepare a solution. Isopropyl alcohol (0.400 g, 6.51 mmol) was added tothe solution under a nitrogen atmosphere while stirring and heating thesolution at 70° C. The mixture was vigorously stirred for 3 hr. Thereaction solution was cooled to room temperature. n-Hexane (10 mL) wasthen added to the cooled reaction solution to carry out extraction forseparation of the mixture into a sulfuric acid layer and an organiclayer, and this extraction was carried out once again. The organiclayers thus obtained were combined, and the combined organic layer waswashed with a saturated aqueous sodium hydrogencarbonate solution andsaturated brine in that order. The solvent was then removed from theorganic layer by distillation to give 666 mg of2-fluoro-4-isopropyl-N-methoxycarbonylaniline as an oil. The oil wasfurther subjected to separation and purification by columnchromatography on silica gel to give 206 mg of2-fluoro-4-isopropyl-N-methoxycarbonylaniline (yield 17.0%).

EI-MS: m/z 212 (M+H)⁺; ¹H NMR (CDCl₃) δ 1.22 (6H, d, J=6.8 Hz,isopropyl-Me), 2.88 (1H, m, isopropyl-CH), 3.80 (3H, s, CH₃), 6.75 (1H,bs, NH), 6.93 (1H, dd, J=12.9, 2.4 Hz, H₃), 6.99 (1H, dd, J=7.8, 2.4 Hz,H₅), 7.95 (1H, bs, H₆).

Example 6 Synthesis of2-fluoro-4-(1-methylcyclohexyl)-N-methoxycarbonylaniline

2-Fluoro-N-methoxycarbonylaniline (3.38 g, 20.0 mmol) prepared asdescribed in Example 1 was dissolved in 77.6% sulfuric acid (20 g) toprepare a solution. 1-Methylcyclohexyl alcohol (2.28 g, 20.0 mol) wasadded dropwise to the solution under a nitrogen atmosphere over a periodof 30 min while stirring and heating the solution at 70° C. After thecompletion of the dropwise addition, the reaction solution wasvigorously stirred at the same temperature for 5 hr. Subsequently, thereaction solution was cooled to room temperature. n-Hexane (100 mL) wasthen added to the cooled reaction solution to carry out extraction forseparation of the mixture into a sulfuric acid layer and an organiclayer. n-Hexane (100 mL) was again added to the sulfuric acid layer tocarry out extraction for separation of an organic layer. The organiclayers thus obtained were combined, and the combined organic layer waswashed with water and saturated brine in that order. The solvent wasthen removed from the organic layer by distillation to give2-fluoro-4-(1-methylcyclohexyl)-N-methoxycarbonylaniline as an oil. Theoil was further subjected to separation and purification by columnchromatography on silica gel to give 843 mg of2-fluoro-4-(1-methylcyclohexyl)-N-ethoxycarbonylaniline as a targetcompound (yield 15.8%, 4-substituted compound: 5-substitutedcompound=100:0).

EI-MS: m/z 265 (M+H)⁺; ¹H NMR (CDCl₃) δ 1.15 (3H, s, 1-methyl), 1.42(4H, m, cyclohexyl), 1.54 (4H, m, cyclohexyl), 1.93 (2H, m, cyclohexyl),3.80 (3H, s, OCH₃), 6.76 (1H, bs, NH), 7.07 (1H, dd, J=13.4, 2.2 Hz,H₃-aromatic), 7.12 (1H, dd, J=8.1, 2.0 Hz, H₅-aromatic), 7.95 (1H, bs,H₆-aromatic).

Example 7 Synthesis of 4-t-butyl-2-fluoro-N-ethoxycarbonylaniline

2-Fluoro-N-ethoxycarbonylaniline (1.00 g, 5.46 mmol) prepared asdescribed in Example 1 was dissolved in 77.6% sulfuric acid (5.00 g) toprepare a solution. t-Butyl alcohol (0.440 g, 6.01 mmol) was addeddropwise to the solution under a nitrogen atmosphere over a period of 30min while stirring and heating the solution at 70° C. After thecompletion of the dropwise addition, the reaction solution wasvigorously stirred at the same temperature for one hr. Thereafter,t-butyl alcohol (0.440 g, 6.01 mmol) was again added dropwise theretoover a period of 30 min. After the completion of the dropwise addition,the reaction solution was vigorously stirred at the same temperature forone hr. t-Butyl alcohol (0.440 g, 6.01 mmol) was again added dropwisethereto over a period of 30 min. After the completion of the dropwiseaddition, the reaction solution was vigorously stirred at the sametemperature for one hr. The reaction solution was cooled to roomtemperature. n-Hexane (10 mL) was then added to the cooled reactionsolution to carry out extraction for separation of the mixture into asulfuric acid layer and an organic layer. n-Hexane (10 mL) was againadded to the sulfuric acid layer to carry out extraction for separationof an organic layer. The organic layers were combined, and the combinedorganic layer was washed with water and saturated brine in that order.The solvent was then removed from the organic layer by distillation togive 1.45 g of N-ethoxycarbonyl-4-t-butyl-2-fluoroaniline as an oilycrude product (yield on weight basis 111%). The crude product wasfurther subjected to separation and purification by columnchromatography on silica gel to give 1.17 g of a mixture of4-t-butyl-2-fluoro-N-ethoxycarbonylaniline with5-t-butyl-2-fluoro-N-ethoxycarbonylaniline (yield90%, 4-t-Bu:5-t-Bu=82:18).

EI-MS:m/z240 (M+H)⁺; ¹H NMR (CDCl₃) δ 1.28 (9H, s, t-Bu), 1.32 (3H, t,J=7.06 Hz, CH₃), 4.24 (2H, q, J=7.06 Hz, CH₂), 6.73 (1H, bs, NH), 7.08(1H, dd, J=13.4, 2.4 Hz, H₃), 7.13 (1H, dd, J=8.8, 2.4 Hz, H₅), 7.95(1H, bs, H₆).

1. A compound of formula (1):

wherein R¹represents branched chain C3-C10 alkyl or optionallysubstituted C3-C10 cycloalkyl; R² represents a halogen atom, optionallysubstituted straight chain or branched chain C1-C8 alkyl, or optionallysubstituted C3-C8 cycloalkyl; R³ represents optionally substitutedstraight chain or branched chain C1-C8 alkyl, optionally substitutedstraight chain or branched chain C2-C6 alkenyl, or optionallysubstituted C3-C8 cycloalkyl; n is an integer of 0 (zero) to 3; and Xrepresents a halogen atom:
 2. The compound according to claim 1, whereinR¹ represents branched chain C3-C5 alkyl or optionally substituted C5-C6cycloalkyl.
 3. The compound according to claim 2, wherein R¹ representsisopropyl, t-butyl, t-amyl, or 1-methylcyclohexyl.
 4. The compoundaccording to any one of claims 1 to 3, wherein R² represents a halogenatom or straight chain or branched chain C1-C4 alkyl.
 5. The compoundaccording to claim 4, wherein R² represents a halogen atom or methyl. 6.The compound according to any one of claims 1 to 3, wherein R³represents optionally substituted straight chain or branched chain C1-C4alkyl, vinyl, isopropenyl, or optionally substituted C5-C6 cycloalkyl.7. The compound according to claim 6, wherein R³ represents methyl orethyl.
 8. The compound according to any one of claims 1 to 3, wherein nis
 0. 9. The compound according to any one of claims 1 to 3, wherein Xrepresents a fluorine atom.
 10. The compound according to claim 1,wherein R¹ represents t-butyl; R³ represents methyl; n is 0; and Xrepresents a fluorine atom.
 11. The compound according to claim 1,wherein R¹ represents t-butyl; R³ represents ethyl; n is 0; and Xrepresents a fluorine atom.
 12. A process for producing the compound offormula (1) as defined in claim 1, comprising the step of reacting the2-haloaniline derivative of the following formula (2) with an alkylatingagent in the presence of an acid catalyst in an organic solvent orsulfuric acid to introduce group R¹, which is as defined in claim 1,into the 4-position of the derivative, thereby preparing the compound offormula (1):

wherein R², R³, n, and X are as defined in claim 1, provided that R² isnot in the 4-position on the aromatic ring.
 13. The process according toclaim 12, wherein the alkylating agent is selected from the groupconsisting of t-butyl alcohol, isobutene, t-butyl chloride, t-butylbromide, isobutyl bromide, and isobutyl chloride.
 14. The processaccording to claim 12, wherein said alkylating agent is t-butyl alcoholand said t-butyl alcohol is used in an amount of 1.0 to 5.0 equivalentsbased on the number of moles of the derivative of formula (2).
 15. Theprocess according to any one of claims 12 to 14, wherein the acidcatalyst is 70 to 90% (w/w) sulfuric acid.
 16. The process according toany one of claims 12 to 14, wherein the acid catalyst is 70 to 90% (w/w)sulfuric acid and the reaction is carried out at a temperature in therange of 60 to 80° C.
 17. The process according to any one of claims 12to 14, which further comprises the step of reacting a compound offormula (4) or its salt with a chloroformic ester ClCOOR³, wherein R³represents optionally substituted straight chain or branched chain C1-C8alkyl, optionally substituted straight chain or branched chain C2-C6alkenyl, or optionally substituted C3-C8 cycloalkyl, under basicconditions to protect amino in the compound of formula (4) or its saltand thus to prepare the 2-haloaniline derivative of formula (2):

wherein R², n, and X are as defined in claim
 1. 18. A process forproducing an aniline derivative of formula (3) or a pharmaceuticallyacceptable salt or solvate thereof, comprising the step of deprotectingthe protected amino in the compound of formula (1) as defined in claim 1under acidic or basic conditions:

wherein n, R¹, R², and X are as defined in claim
 1. 19. The processaccording to claim 18, wherein, in formula (3), R¹ represents t-butyl; nis 0; and X represents a fluorine atom.
 20. The process according toclaim 18, wherein the deprotection reaction is carried out by heatingthe compound of formula (1) in a 20 to 53% aqueous sodium hydroxidesolution or a 20 to 47% aqueous potassium hydroxide solution.
 21. Theprocess according to any one of claims 18 to 20, which further comprisesthe step of reacting a 2-haloaniline derivative of formula (2) with analkylating agent in the presence of an acid catalyst in an organicsolvent or sulfuric acid to introduce group R¹, which is as defined inclaim 1, into the 4-position of the derivative, thereby preparing thecompound of formula (1):

wherein R², R³, n, and X are as defined in claim 1, provided that R² isnot in the 4-position on the aromatic ring.
 22. The process according toclaim 15, which further comprises the step of reacting a compound offormula (4) or its salt with a chloroformic ester ClCOOR³, wherein R³represents optionally substituted straight chain or branched chain C1-C8alkyl, optionally substituted straight chain or branched chain C2-C6alkenyl, or optionally substituted C3-C8 cycloalkyl, under basicconditions to protect amino in the compound of formula (4) or its saltand thus to prepare the 2-haloaniline derivative of formula (2):

wherein R², n, and X are as defined in claim
 1. 23. The processaccording to claim 16, which further comprises the step of reacting acompound of formula (4) or its salt with a chloroformic ester ClCOOR³,wherein R³ represents optionally substituted straight chain or branchedchain C1-C8 alkyl, optionally substituted straight chain or branchedchain C2-C6 alkenyl, or optionally substituted C3-C8 cycloalkyl, underbasic conditions to protect amino in the compound of formula (4) or itssalt and thus to prepare the 2-haloaniline derivative of formula (2):

wherein R², n, and X are as defined in claim 1.